Obesity is a multivariate disease which has reached epidemic proportions. The neurochemical basis of excessive body weight (BW) gain due to a positive imbalance in energy intake over expenditure, is virtually unknown.. Excessive BW gain may result either from hyperphagia due to impaired signaling in the interconnected appetite regulating network (ARN) in the hypothalamus or it may be of dietary origin, with our without hyperphagia. The objectives of this proposal are to identify the neurochemical disruptions and rearrangements (plasticity) at various loci in the ARN and leptin feedback that underlie excessive BW gain. In Aim 1, to test the hypothesis that up-regulation of the daily pattern of orexigenic signaling in the ARN is responsible for hyperphagia, we will assess (a) synthesis (gene expression and levels of NPY, GAL, and AGRP) in well characterized and novel hypothalamic sites; (b) activity (food-intake in response to administration of these peptides and antagonists); and (c) receptor gene expression in novel hypothalamic sites. Aim 2 will test the hypothesis that alteration of the tonic restraint exercised by central anorexigenic signals (CART and the melanocortin, alphaMSH) contributes to hyperphagia. Aim 3 will test the hypothesis that leptin signaling is altered during hyperphagia by analyzing changes in the daily pattern of leptin gene expression in adipocytes, plasma leptin levels and leptin receptor mRNA in discrete hypothalamic sites and the response to leptin administration. To test these three interrelated hypotheses, we propose to employ a rat model of hyperphagia produced by destruction of the paraventricular nucleus, the target site of action of orexigenic and anorexigenic peptides originating in the arcuate nucleus of the hypothalamus. Finally, in Aim 4, we propose to determine whether similar mechanisms operate in diet-induced obesity. Since the development of effective therapeutic strategies for humans requires a complete understanding of the impairment in neurochemical loci, this proposal to elucidate the neurochemical etiology of hyperphagia and excessive BW gain in rodents models is designed to meet this goal.